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CTRP6 is an endogenous complement regulator that can effectively treat induced arthritis

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  • Masanori A. Murayama

    (Center for Animal Disease Models, Research Institute for Biomedical Sciences, Tokyo University of Science
    Laboratory of Molecular Pathogenesis, Center for Experimental Medicine and Systems Biology, The Institute of Medical Science, The University of Tokyo (IMSUT)
    Graduate School of Frontier Sciences, The University of Tokyo
    Core Research for Evolutional Science and Technology (CREST), Japan Science and Technology Agency (JST))

  • Shigeru Kakuta

    (Laboratory of Molecular Pathogenesis, Center for Experimental Medicine and Systems Biology, The Institute of Medical Science, The University of Tokyo (IMSUT)
    Present addresses: Department of Biomedical Science, Graduate School of Agricultural and Life Sciences, The University of Tokyo, Tokyo 113-8657, Japan (S.K.); Department of Molecular Pharmacology and Neuroscience, Nagasaki University Graduate School of Biomedical Sciences, 1-14 Bunkyo-machi, Nagasaki 852-8521, Japan (T.Y.); Division of Immune Regulation, Institute for Genome Research, University of Tokushima, Tokushima 770-8503, Japan (T.M.); Laboratory for Tissue Dynamics, Center for Integrative Medical Sciences, RIKEN, Yokohama 230-0045, Japan (H.I.); Department of Biochemistry and Molecular Biology, Graduate School and Faculty of Medicine, The University of Tokyo, Tokyo 113-0033, Japan (N.S.); Stem Cell Research Center, Renji Hospital Shanghai Jiao Tong University School of Medicine, Shanghai 200127, China (Y.L.))

  • Asuka Inoue

    (Faculty of Medicine, University of Tsukuba)

  • Naoto Umeda

    (Faculty of Medicine, University of Tsukuba)

  • Tomo Yonezawa

    (Center for Animal Disease Models, Research Institute for Biomedical Sciences, Tokyo University of Science
    National Research Institute of Child Health and Development
    Present addresses: Department of Biomedical Science, Graduate School of Agricultural and Life Sciences, The University of Tokyo, Tokyo 113-8657, Japan (S.K.); Department of Molecular Pharmacology and Neuroscience, Nagasaki University Graduate School of Biomedical Sciences, 1-14 Bunkyo-machi, Nagasaki 852-8521, Japan (T.Y.); Division of Immune Regulation, Institute for Genome Research, University of Tokushima, Tokushima 770-8503, Japan (T.M.); Laboratory for Tissue Dynamics, Center for Integrative Medical Sciences, RIKEN, Yokohama 230-0045, Japan (H.I.); Department of Biochemistry and Molecular Biology, Graduate School and Faculty of Medicine, The University of Tokyo, Tokyo 113-0033, Japan (N.S.); Stem Cell Research Center, Renji Hospital Shanghai Jiao Tong University School of Medicine, Shanghai 200127, China (Y.L.))

  • Takumi Maruhashi

    (Center for Animal Disease Models, Research Institute for Biomedical Sciences, Tokyo University of Science
    Laboratory of Molecular Pathogenesis, Center for Experimental Medicine and Systems Biology, The Institute of Medical Science, The University of Tokyo (IMSUT)
    Present addresses: Department of Biomedical Science, Graduate School of Agricultural and Life Sciences, The University of Tokyo, Tokyo 113-8657, Japan (S.K.); Department of Molecular Pharmacology and Neuroscience, Nagasaki University Graduate School of Biomedical Sciences, 1-14 Bunkyo-machi, Nagasaki 852-8521, Japan (T.Y.); Division of Immune Regulation, Institute for Genome Research, University of Tokushima, Tokushima 770-8503, Japan (T.M.); Laboratory for Tissue Dynamics, Center for Integrative Medical Sciences, RIKEN, Yokohama 230-0045, Japan (H.I.); Department of Biochemistry and Molecular Biology, Graduate School and Faculty of Medicine, The University of Tokyo, Tokyo 113-0033, Japan (N.S.); Stem Cell Research Center, Renji Hospital Shanghai Jiao Tong University School of Medicine, Shanghai 200127, China (Y.L.))

  • Koichiro Tateishi

    (Tokai University)

  • Harumichi Ishigame

    (Laboratory of Molecular Pathogenesis, Center for Experimental Medicine and Systems Biology, The Institute of Medical Science, The University of Tokyo (IMSUT)
    Present addresses: Department of Biomedical Science, Graduate School of Agricultural and Life Sciences, The University of Tokyo, Tokyo 113-8657, Japan (S.K.); Department of Molecular Pharmacology and Neuroscience, Nagasaki University Graduate School of Biomedical Sciences, 1-14 Bunkyo-machi, Nagasaki 852-8521, Japan (T.Y.); Division of Immune Regulation, Institute for Genome Research, University of Tokushima, Tokushima 770-8503, Japan (T.M.); Laboratory for Tissue Dynamics, Center for Integrative Medical Sciences, RIKEN, Yokohama 230-0045, Japan (H.I.); Department of Biochemistry and Molecular Biology, Graduate School and Faculty of Medicine, The University of Tokyo, Tokyo 113-0033, Japan (N.S.); Stem Cell Research Center, Renji Hospital Shanghai Jiao Tong University School of Medicine, Shanghai 200127, China (Y.L.))

  • Rikio Yabe

    (Center for Animal Disease Models, Research Institute for Biomedical Sciences, Tokyo University of Science
    Laboratory of Molecular Pathogenesis, Center for Experimental Medicine and Systems Biology, The Institute of Medical Science, The University of Tokyo (IMSUT)
    Medical Mycology Research Center, Chiba University)

  • Satoshi Ikeda

    (Laboratory of Molecular Pathogenesis, Center for Experimental Medicine and Systems Biology, The Institute of Medical Science, The University of Tokyo (IMSUT))

  • Akimasa Seno

    (Center for Animal Disease Models, Research Institute for Biomedical Sciences, Tokyo University of Science
    Laboratory of Molecular Pathogenesis, Center for Experimental Medicine and Systems Biology, The Institute of Medical Science, The University of Tokyo (IMSUT)
    Graduate School of Frontier Sciences, The University of Tokyo)

  • Hsi-Hua Chi

    (Center for Animal Disease Models, Research Institute for Biomedical Sciences, Tokyo University of Science)

  • Yuriko Hashiguchi

    (Center for Animal Disease Models, Research Institute for Biomedical Sciences, Tokyo University of Science)

  • Riho Kurata

    (Center for Animal Disease Models, Research Institute for Biomedical Sciences, Tokyo University of Science
    National Research Institute of Child Health and Development)

  • Takuya Tada

    (Laboratory of Molecular Pathogenesis, Center for Experimental Medicine and Systems Biology, The Institute of Medical Science, The University of Tokyo (IMSUT))

  • Sachiko Kubo

    (Center for Animal Disease Models, Research Institute for Biomedical Sciences, Tokyo University of Science
    Laboratory of Molecular Pathogenesis, Center for Experimental Medicine and Systems Biology, The Institute of Medical Science, The University of Tokyo (IMSUT))

  • Nozomi Sato

    (Laboratory of Molecular Pathogenesis, Center for Experimental Medicine and Systems Biology, The Institute of Medical Science, The University of Tokyo (IMSUT)
    Present addresses: Department of Biomedical Science, Graduate School of Agricultural and Life Sciences, The University of Tokyo, Tokyo 113-8657, Japan (S.K.); Department of Molecular Pharmacology and Neuroscience, Nagasaki University Graduate School of Biomedical Sciences, 1-14 Bunkyo-machi, Nagasaki 852-8521, Japan (T.Y.); Division of Immune Regulation, Institute for Genome Research, University of Tokushima, Tokushima 770-8503, Japan (T.M.); Laboratory for Tissue Dynamics, Center for Integrative Medical Sciences, RIKEN, Yokohama 230-0045, Japan (H.I.); Department of Biochemistry and Molecular Biology, Graduate School and Faculty of Medicine, The University of Tokyo, Tokyo 113-0033, Japan (N.S.); Stem Cell Research Center, Renji Hospital Shanghai Jiao Tong University School of Medicine, Shanghai 200127, China (Y.L.))

  • Yang Liu

    (Laboratory of Molecular Pathogenesis, Center for Experimental Medicine and Systems Biology, The Institute of Medical Science, The University of Tokyo (IMSUT)
    Present addresses: Department of Biomedical Science, Graduate School of Agricultural and Life Sciences, The University of Tokyo, Tokyo 113-8657, Japan (S.K.); Department of Molecular Pharmacology and Neuroscience, Nagasaki University Graduate School of Biomedical Sciences, 1-14 Bunkyo-machi, Nagasaki 852-8521, Japan (T.Y.); Division of Immune Regulation, Institute for Genome Research, University of Tokushima, Tokushima 770-8503, Japan (T.M.); Laboratory for Tissue Dynamics, Center for Integrative Medical Sciences, RIKEN, Yokohama 230-0045, Japan (H.I.); Department of Biochemistry and Molecular Biology, Graduate School and Faculty of Medicine, The University of Tokyo, Tokyo 113-0033, Japan (N.S.); Stem Cell Research Center, Renji Hospital Shanghai Jiao Tong University School of Medicine, Shanghai 200127, China (Y.L.))

  • Masahira Hattori

    (Graduate School of Frontier Sciences, The University of Tokyo)

  • Shinobu Saijo

    (Laboratory of Molecular Pathogenesis, Center for Experimental Medicine and Systems Biology, The Institute of Medical Science, The University of Tokyo (IMSUT)
    Medical Mycology Research Center, Chiba University)

  • Misao Matsushita

    (Tokai University)

  • Teizo Fujita

    (Fukushima Prefectural General Hygiene Institute)

  • Takayuki Sumida

    (Faculty of Medicine, University of Tsukuba)

  • Yoichiro Iwakura

    (Center for Animal Disease Models, Research Institute for Biomedical Sciences, Tokyo University of Science
    Laboratory of Molecular Pathogenesis, Center for Experimental Medicine and Systems Biology, The Institute of Medical Science, The University of Tokyo (IMSUT)
    Graduate School of Frontier Sciences, The University of Tokyo
    Core Research for Evolutional Science and Technology (CREST), Japan Science and Technology Agency (JST))

Abstract

The complement system is important for the host defence against infection as well as for the development of inflammatory diseases. Here we show that C1q/TNF-related protein 6 (CTRP6; gene symbol C1qtnf6) expression is elevated in mouse rheumatoid arthritis (RA) models. C1qtnf6−/− mice are highly susceptible to induced arthritis due to enhanced complement activation, whereas C1qtnf6-transgenic mice are refractory. The Arthus reaction and the development of experimental autoimmune encephalomyelitis are also enhanced in C1qtnf6−/− mice and C1qtnf6−/− embryos are semi-lethal. We find that CTRP6 specifically suppresses the alternative pathway of the complement system by competing with factor B for C3(H2O) binding. Furthermore, treatment of arthritis-induced mice with intra-articular injection of recombinant human CTRP6 cures the arthritis. CTRP6 is expressed in human synoviocytes, and CTRP6 levels are increased in RA patients. These results indicate that CTRP6 is an endogenous complement regulator and could be used for the treatment of complement-mediated diseases.

Suggested Citation

  • Masanori A. Murayama & Shigeru Kakuta & Asuka Inoue & Naoto Umeda & Tomo Yonezawa & Takumi Maruhashi & Koichiro Tateishi & Harumichi Ishigame & Rikio Yabe & Satoshi Ikeda & Akimasa Seno & Hsi-Hua Chi , 2015. "CTRP6 is an endogenous complement regulator that can effectively treat induced arthritis," Nature Communications, Nature, vol. 6(1), pages 1-12, December.
    • Handle: RePEc:nat:natcom:v:6:y:2015:i:1:d:10.1038_ncomms9483
    DOI: 10.1038/ncomms9483
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